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- Title
Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias.
- Authors
Frankel, A E; McCubrey, J A; Miller, M S; Delatte, S; Ramage, J; Kiser, M; Kucera, G L; Alexander, R L; Beran, M; Tagge, E P; Kreitman, R J; Hogge, D E
- Abstract
Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G4S)2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) > or =10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocyte-macrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three- to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease.
- Subjects
DIPHTHERIA toxin; INTERLEUKIN-3; MYELOID leukemia; ANTINEOPLASTIC agents; BACTERIAL toxins; CELL receptors; COMPARATIVE studies; DNA; DRUG resistance in cancer cells; CLINICAL drug trials; RESEARCH methodology; MEDICAL cooperation; POLYMERASE chain reaction; PROTEINS; RECOMBINANT proteins; RESEARCH; STEM cells; EVALUATION research; CANCER cell culture; COLONY-forming units assay
- Publication
Leukemia (08876924), 2000, Vol 14, Issue 4, p576
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/sj.leu.2401743